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Integration in oncogenes plays only a minor role in determining the in vivo distribution of HIV integration sites before or during suppressive antiretroviral therapy
- Source :
- PLoS Pathogens, Vol 17, Iss 4, p e1009141 (2021), PLoS Pathogens
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- HIV persists during antiretroviral therapy (ART) as integrated proviruses in cells descended from a small fraction of the CD4+ T cells infected prior to the initiation of ART. To better understand what controls HIV persistence and the distribution of integration sites (IS), we compared about 15,000 and 54,000 IS from individuals pre-ART and on ART, respectively, with approximately 395,000 IS from PBMC infected in vitro. The distribution of IS in vivo is quite similar to the distribution in PBMC, but modified by selection against proviruses in expressed genes, by selection for proviruses integrated into one of 7 specific genes, and by clonal expansion. Clones in which a provirus integrated in an oncogene contributed to cell survival comprised only a small fraction of the clones persisting in on ART. Mechanisms that do not involve the provirus, or its location in the host genome, are more important in determining which clones expand and persist.<br />Author summary In HIV-infected individuals, a small fraction of the infected cells persist and divide. This reservoir persists during fully suppressive ART and can rekindle the infection if ART is discontinued. Because the number of possible sites of HIV DNA integration is very large, each infected cell, and all of its descendants, can be identified by the site where the provirus is integrated (IS). To understand the selective forces that determine the fates of infected cells in vivo, we compared the distribution of HIV IS in freshly-infected cells to cells from HIV-infected donors sampled both before and during ART. We found that, as previously reported, integration favors highly-expressed genes. However, over time, the fraction of cells with proviruses integrated in highly-expressed genes decreases, implying that they grow less well. There are exceptions to this broad negative selection. When a provirus is integrated in a specific region in one of seven genes, the proviruses affect the expression of the target gene, promoting growth and/or survival of the cell. Although this effect is striking, it is only a minor component of the forces that promote the growth and survival of the population of infected cells during ART.
- Subjects :
- CD4-Positive T-Lymphocytes
RNA viruses
HIV integration
Gene Expression
HIV Infections
Virus Replication
Pathology and Laboratory Medicine
Proviruses
Immunodeficiency Viruses
Medicine and Health Sciences
Public and Occupational Health
Biology (General)
0303 health sciences
030302 biochemistry & molecular biology
Genomics
Provirus
Vaccination and Immunization
Anti-Retroviral Agents
Medical Microbiology
Viral Pathogens
Viruses
Pathogens
Research Article
QH301-705.5
Immunology
DNA transcription
Antiretroviral Therapy
Biology
Research and Analysis Methods
Genome Complexity
Peripheral blood mononuclear cell
Microbiology
Human Genomics
03 medical and health sciences
Antiviral Therapy
In vivo
Virology
Retroviruses
Genetics
Distribution (pharmacology)
Humans
Molecular Biology Techniques
Gene
Microbial Pathogens
Molecular Biology
030304 developmental biology
Oncogene
Lentivirus
Organisms
Biology and Life Sciences
HIV
Computational Biology
Oncogenes
RC581-607
In vitro
Introns
DNA, Viral
Leukocytes, Mononuclear
Parasitology
Preventive Medicine
Immunologic diseases. Allergy
Cloning
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 17
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....ca6d712754ea98f0ea1c406eeb88f922